SPECIES-DIFFERENCES IN 5-ALPHA-ANDROSTANE-3-BETA, 17-BETA-DIOL HYDROXYLATION BY RAT, MONKEY, AND HUMAN PROSTATE MICROSOMES

The 6α-, 7α-, and 7β-hydroxylation of 5α-androstane-3β,17β-diol by rat prostate microsomes appears to be catalyzed by a single, high-affinity cytochrome P450 enzyme. In the present study we have examined the hydroxylation of 5α-androstane-3β,17β-diol by prostate microsomes from cynomolgus monkeys and from normal subjects and patients with benign prostatic hyperplasia. Our results suggest that although rat, monkey, and human prostate microsomes catalyze the 6α-, 7α-, and 7β-hydroxylation of 5α-androstane-3β,17β-diol, these pathways of oxidation in monkeys and humans are not catalyzed by a single cytochrome P450 enzyme. The ratio of the three metabolites was not uniform among prostate microsomal samples from individual humans or monkeys. The 6α-hydroxylation of 5α-androstane-3β,17β-diol varied independently of both the 7α- and 7β-hydroxylation, which varied in unison. The 6α-, 7α-, and 7β-hydroxylation of 5α-androstane-3β,17β-diol by monkey prostate microsomes appeared to be differentially affected by in vivo treatment of monkeys with β-naphthoflavone or dexamethasone. Treatment of a monkey with dexamethasone appeared to cause a 2.5-fold increase in both the 7α- and the 7β-hydroxylation of 5α-androstane-3β,17β-diol without increasing the 6α-hydroxylation. The 7α- and 7β-hydroxylation of 5α-androstane-3β,17β-diol by human and monkey prostate microsomes, but not the 6α-hydroxylation, was inhibited by antibody against rat liver NADPH-cytochrome P450 reductase. Similarly, the 7α- and 7β-hydroxylation of 5α-androstane-3β,17β-diol by human prostate microsomes, but not the 6α-hydroxylation, was markedly inhibited (>85%) by equimolar concentrations of the imidazole-containing antimycotic drugs ketoconazole, clotrimazole, and miconazole. These results suggest that the 7α- and 7β-hydroxylation of 5α-androstane-3β,17β-diol by monkey and human prostate microsomes is catalyzed by a cytochrome P450 enzyme, whereas the 6α-hydroxylation is catalyzed by a different enzyme which may or may not be a cytochrome P450 monooxygenase. The hydroxylation of 5α-androstane-3β,17β-diol by prostate microsomes from normal human subjects was quantitatively and qualitatively similar to its hydroxylation by prostate microsomes from patients with benign prostatic hyperplasia. This suggests that an impairment of androgen inactivation is not the mechanism for the proposed accumulation of 5α-dihydrotestosterone in the hyperplastic prostate. The rate of 5α-androstane-3β,17β-diol hydroxylation by human prostate microsomes ranged from 1 to 10 pmol/mg protein/min, which is considerably less than the rate catalyzed by rat prostate microsomes (~600 pmol/mg protein/min). This marked species difference in the rate of inactivation of androgens by prostate microsomes could potentially explain why humans, in contrast to rats, are prone to develop benign prostatic hyperplasia. © 1992.